Pyridopyrazine derivatives for treating alcohol and nicotine abuse and addiction

ABSTRACT

Racemic or optically active pyrido[1,2-a]pyrazine derivatives of the formula ##STR1## wherein X is N or CH and Y represents one of certain pyrazolo, triazolo, tetrazolo or cyclic imido radicals are useful in the treatment of abuse of and/or addiction to such substances as narcotics, alcohol and nicotine.

This is a continuation of application Ser. No. 07/969,843, filed asPCT/US91/03749 May 28, 1991, and PCT/US90/03708 on Jun. 29, 1990, nowabandoned.

BACKGROUND OF THE INVENTION

The present invention is directed to the use of certain racemic andoptically active pyrido[1,2-a]-pyrazine derivatives, also described asbis-azabicyclic compounds and defined by the formula (I) below in thetreatment of abuse of and addiction to such substances as narcotics,alcohol, nicotine and amphetamines. The compounds of the formula (I) andtheir use in the treatment of anxiety and depression are the subjects ofcopending International application nos. PCT/US89/00275, filed Jan. 26,1989, and PCT/US89/03811, filed Sep. 1, 1989.

Recently a number of1-(2-pyrimidinyl)-4-[4-(cyclic-imido)butyl]piperidine derivatives havebeen disclosed as anxiolytic agents which are generally lacking sedativeactivity. Among these are buspirone, where the cyclic-imido group is4,4-tetramethylene-piperidine-2,6-dion-1-yl (Wu et al., U.S. Pat. Nos.3,717,634 and 3,907,801; Casten et al., U.S. Pat. Nos. 4,182,763);gepirone, where the group is 4,4-dimethylpiperidine-2,6-dion-1-yl(Temple, Jr., U.S. Pat. No. 4,423,049); and ipsapirone, where the groupis 1,1-dioxobenzo[d]isothiazol-3(2H)-on-2-yl (Dompert et al., Germanpatent publication 3,321,969-Al). See also Ishizumi et al., U.S. Pat.Nos. 4,507,303 and 4,543,355; Freed et al., U.S. Pat. 4,562,255; Stacket al., U.S. Pat. No. 4,732,983; New et al., U.S. Pat. No. 4,524,026;and Stack, U.S. Pat. No. 4,788,290.

Such agents as busipirone and gepirone have now been shown to possessantidepressant activity [Schweizer et al., Psychopharm. Bull., v. 22,pp. 183-185 (1986); Amsterdam et al., Current. Therap. Res., v. 41, pp.185-193 (1987); and Stack, U.S. Pat. No. 4,788,290]; and most recently,to be of value in the treatment of substance addiction, such asover-eating, tobacco addiction and drug abuse (published European patentapplication EP-A-356,997).

The present bis-aza-bicyclic compounds generally show minimal in vivostimulation of dopaminergic systems, reflective of reduced or minimalneurological side effects in the clinical use of these compounds.

SUMMARY OF THE INVENTION

The present invention is directed to the use of certain bis-aza-bicycliccompounds, vii., racemic or optically active compounds of the formula##STR2## and the pharmaceutically acceptable acid addition saltsthereof, wherein X is N or CH;

Y is ##STR3## Z is ##STR4## SCH₂, OCH₂, --Y¹ (CH₂)_(n) or Y¹ (CH₂)_(n)substituted on carbon with up to 2 methyl groups;

n is 1 or 2; and

y¹ is CH₂, NH or NCH₃ ;

in the treatment of substance abuse or addiction in a mammal, includingman.

In the compounds of the formula (I), for ease of preparation and goodactivity, Y is preferably ##STR5##

A particularly preferred compound is that wherein Z is Y¹ (CH₂)_(n), Y¹is CH₂, n is 1 and X is N.

The nomenclature employed herein is that of the I.U.P.A.C., Nomenclatureof Organic Chemistry, 1979 Ed., Pergammon Press, New York. Alternativenames for the nucleus of the present bis-aza-bicyclic compounds areperhydro-1H-pyrido[1,2-a]pyrazine, 2,4a-diazaperhydronaphthalene, and1,4-diazabicyclo[5.5.0]decane.

Said pharmaceutically acceptable acid addition salts include but are notlimited to those with HCl, HNO₃, H₂ SO₄, H₃ PO₄, pCH₃ C₆ H₄ SO₃ H orHOOCCH₂ CH₂ COOH. These salts are prepared by conventional methods, forexample, by combining molar equivalent amounts of a compound of theformula (I) and the appropriate acid in a solvent from which the desiredsalt is of low solubility and precipitates directly, or from which thesalt can be isolated by concentration or addition of a non-solvent.

The present invention also encompasses pharmaceutical compositionscomprising an amount of a compound of the formula (I) which is effectivein the treatment of substance abuse or addiction.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the above formula (I) are readily prepared by a numberof methods. One general method, which is the preferred method for allracemic compounds and the preferred method for optically activecompounds when Y is other than an imido group, is to displace thesulfonate ester group of a racemic or optically active compound of theformula ##STR6## with an anion Y⁻ , wherein R, X and Y are as definedabove, and Y⁻ represents the anion of a salt MY where M is most simplyan alkali metal such as sodium. When the required salt is not availablecommercially, as is most frequently the case, it is convenient to formthe required salt in situ in the form of the sodium salt, e.g.,irreversibly by the action of sodium hydride on the compound of theformula Y--H; or reversibly by reaction with a base such as Na₂ CO₃which is not itself nucleophilic. This process is representative of suchdisplacement reactions in general. It is generally carried out in areaction inert-solvent, preferably one which is aprotic and certainlyone which is less acidic than the compound Y--H. Particularly usefulsolvents in the present instance are acetonitrile and dimethylformamide.Temperature is not generally critical in this process, but, in order toachieve complete conversion within a reasonably short period of time,elevated temperatures, e.g., 90°-120° C., are generally preferred. Alsofor the purpose of forcing this second order displacement reaction tocompletion within a reasonable period of time, a molar excess of one ofthe reactants, usually the more readily available salt, MY, is generallyemployed in this process. Methyl is the preferred value of R in thisprocess, for ease of preparation of the mesylate ester and for thefacile displacement of the mesylate anion. The product is isolated byconventional methods of concentration, evaporation, extraction,chromatography and crystallization, with, if direct formation of an acidaddition salt is desired, addition of an appropriate acid in anappropriate amount, e.g., addition of one molar equivalent of HCl if themono-hydrochloride salt is desired.

As used in the preceding paragraph and elsewhere herein, the expression"reaction-inert" solvent refers to a solvent which does not interactwith reactants, reagents, intermediates or products in a manner whichadversely affects the yield of the desired product.

A second general method for preparation of compounds of the formula (I)is to directly couple an alcohol of the formula ##STR7## with theheterocycle or imide of the formula YH, where again X and Y are asdefined above. The preferred coupling reagent is an approximately 1:1molar mixture diethyl azodicarboxylate and triphenylphosphine. Usually,about 2 to 2.1 molar equivalents of these reagents are used in couplingequimolar amounts of YH and the alcohol (V). The preferred solvents arerelatively polar ethers such as tetrahydrofuran, dioxane or1,2-dimethoxyethane, the first of these being particularly well-suited.Temperature is not critical, although somewhat elevated temperatures(e.g., the reflux temperature of tetrahydrofuran) are preferred, inorder to achieve complete reaction in a reasonable period of time.

The compounds of the formula (I) wherein the group Y is an imido groupare also generally prepared from the corresponding amine of the formula##STR8## by the action of an anhydride of the formula ##STR9## wherein Xand Z are as defined above. This is the preferred method for preparationof optically active compounds of the formula (I) when Y is an imidogroup (excluding those compounds wherein the group Z contains an NHgroup, where the anhydride has the potential to polymerize). Accordingto this alternative method, the amine (VI) and the anhydride (VII),generally in about molar equivalents, are heated to about 100°-160° C.in a reaction inert solvent. Particularly well suited as solvent hereare mixed xylenes boiling in the range of about 138°-142° C. Thereaction is then conveniently carried out at the reflux temperature ofsaid mixed xylenes.

The required racemic and optically active starting materials of theabove formulas (IV), (V) and (VI) are prepared via the synthetic routessummarized in Flowsheet 1. While the overall route and the variousintermediates are novel, the individual chemical steps are generallyanalogous to known chemical transformations. Generally suitableconditions are found in the prior art. Particularly well-suitedconditions are exemplified below. ##STR10##

The value of the present compounds in the treatment of substance abuseor addiction is determined by the use of animal models which arewell-established in the art. For example, see:

In General: Schuster, C. R., and Johansen, C. E., The Use of AnimalModels for the Study of Drug Abuse. In: R. J. Gibbens, Y. Israel, H.Kalant, R. E. Popham, W. Schmidt, and R. G. Smart (Eds.) ResearchAdvances in Alcohol and Drug Problems, Vol. 1, pp. 1-31, John Wiley andSons, New York, 1974.

Re Stimulants: Johansen, C. E., and Schuster, C. R., Procedures for thePreclinical Assessment of Abuse Potential of Psychotropic Drugs inAnimals. In: Predicting Dependence Liability of Stimulant and DepressantDrugs, Eds. Travis Thompson and Klaus Unna. pp. 203-229 University ParkPress, Baltimore, 1977.

Re Opiates: Weeks, J. R., Experimental Morphine Addiction: Method forAutomatic Intravenous Injections in Unrestrained Rats, Science, 138:143-144 (1962).

Re Alcohol: Altshuler, H. L., Phillips, P. E., and Feinhandler, D. A.,Alteration of Ethanol Self-administration by Naltrexone, Life Sci. , 26:679-688 (1980).

Re Nicotine: Goldberg, S. R., Spealman, R. D., and Goldberg, D. M.,Persistent High-rate Behavior Maintained by IntraveousSelf-administration of Nicotine, Science, 214: 573-575 (1981).

For use in treating substance abuse and alleviating the symptoms ofanxiety or addiction in a human subject, a compound of the formula (I),or a pharmaceutically-acceptable salt thereof, is administered in anamount of about 2-200 mg/day, in single or divided daily doses. Inparticular cases, dosages outside that range are prescribed at thediscretion of the attending physician. The preferred route ofadministration is generally oral, but parenteral administration (e.g.,intramuscular, intravenous, intradermal) will be preferred in specialcases, e.g., where oral absorption is impaired as by disease, or thepatient is unable to swallow.

The compounds of the present invention are generally administered in theform of pharmaceutical compositions comprising at least one of thecompounds of the formula (I), or a salt thereof, together with apharmaceutically acceptable vehicle or diluent. Such compositions aregenerally formulated in a conventional manner utilizing solid or liquidvehicles or diluents as appropriate to the mode of desiredadministration: for oral administration, in the form of tablets, hard orsoft gelatin capsules, suspensions, granules, powders and the like; and,for parenteral administration, in the form of injectable solutions orsuspensions, and the like.

The present invention is illustrated by the following examples, but isnot limited to the details thereof.

EXAMPLE 1cis-2-(2-Pyrimidinyl)-7-(succinimidomethyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

Method A

A flame-dried flask fitted with magnetic stirring and a nitrogen inletwas charged with succinimide (0.95 g; 9.6 mmol) in dry dimethylformamide(25 ml). Sodium hydride (0.49 g of 60% mineral oil dispersion; 12.2mmol) was added all at once, and the resulting mixture was stirred andheated at 70° C. for 1 hour.cis-7-(Methanesulfonyloxymethyl)-2-(2-pyrimidyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (1.56 g; 4.8 retool) was added, andthe stirred mixture heated at 110° C. for 18 hours. Concentration invacuo afforded a solid, which was dissolved in 25 ml of CH₂ Cl₂. Anequal volume of water was added, and the pH of the well-stirred mixturewas adjusted to 2.0 (6N HCl). The separated organic phase was extracteda second time with an equal volume of water at pH 2.0. Finally, theorganic phase was extracted with an equal volume of water at pH 10.0(saturated Na₂ CO₃). The basic aqueous phase was separated, andextracted 2×150 ml CH₂ Cl₂. The latter organic layers were combined,treated with activated carbon, dried (Na₂ SO₄) and concentrated in vacuoto afford a colorless amorphous foam, which was crystallized from 35 mlof isopropanol to afford 1.14 g (72%) of title compound as colorlesscrystals, mp 183°-184° C. TLC Rf 0.43 (9:1 CH₂ Cl₂ : CH₃ OH). HRMS329.1906, calcd. 329.1854.

¹³ C-NMR(250MHz, CDCl₃) delta 177.4, 161.4, 157.7, 109.6, 61.0, 57.9,54.7, 48.8, 43.5, 40.7, 32.2, 28.1 24.9, 24.4

Method B

To a magnetically stirred solution of triphenylphosphine (262 mg, 1.0retool) and diethylazodicarboxylate (0.174 ml, 192 mg, 1.05 mmol) in 8ml of dry tetrahydrofuran, a solution consisting of succinimide (99 mg,1.0 mmol) andcis-7-(hydroxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine(248mg, 1.0 mmol) in 20 ml of dry tetrahydrofuran was added dropwise overone hour. The reaction was refluxed for 18 hours; and then concentratedin vacuo to an oil. The oil was dissolved in methylene chloride/watermixture (35 ml of each). The pH of the well-stirred mixture was thenadjusted to 2 with 6N HCl , and the phases were then separated. Theorganic phase was combined with 10 ml of water, and the pH of themixture likewise adjusted to 2. The two acidic aqueous extracts werecombined and stirred with an equal volume of methylene chloride whilethe pH was adjusted to 10 with saturated Na₂ CO₃. The phases wereseparated and the aqueous phase was extracted twice with fresh 50 mlportions of methylene chloride. The three organic extracts werecombined, treated with activated carbon, dried (Na₂ SO₄) and stripped toan oil which was crystallized from isopropanol to yield 31 mg (9.5%) ofpresent title product identical with that of Method A.

Method C

A solution ofcis-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine(149mg, 0.6 retool), succinic anhydride (60 mg, 0.6 mmol) in xylenes (9 ml,constant boiling range 138°-142° C.) was refluxed for 18 hours. Thereaction was concentrated in vacuo to an oil, which was taken up inmethylene chloride (30 ml). An equal volume of water was added, and thepH of the well-stirred mixture adjusted to 2.0 (6N HCl). The phases wereseparated, and the organic phase was extracted with a fresh portion ofwater at pH 2. The combined acidic extracts were stirred with methylenechloride (40 ml) with the pH adjusted to 10.0 (saturated Na₂ CO₃). Thephases were separated, and the aqueous phase was extracted twice withfresh 40 ml portions of methylene chloride. The basic organic extractswere combined, treated with activated carbon, dried (Na₂ SO₄) andconcentrated in vacuo to a solid which was crystallized from 7 ml ofisopropanol to yield 164 mg (83%) of the title compound as colorlesscrystals, identical with the products of methods A and B.

EXAMPLE 2 cis-7-(Substitutedmethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazines

The following additional title compounds were prepared according toMethod A of the preceding Example, substituting the appropriate imide orheterocycle for succinimide. Shown is the substituent, its yield, andits properties. All ¹³ C-NMR indicate values at 300 MHz in CDCl₃, unlessotherwise specified. If unspecified, the TLC eluant was 9:1 CH₂ Cl₂ :CH₃OH on 0.25 mm silica gel 60F₂₅₄ plates. 3,3,4-Trimethylsuccinimido(9.7%); crystallized from ethyl acetate:hexane; TLC Rf 0.58; HRMS371.2274, calcd. 371. 2321.

¹³ C-NMR 183.2, 179.4, 161.3, 157.6, 109.5, 60.9, 57.9, 54.7, 48.8,45.8, 43.5, 43.0, 40.2, 32.3, 32.1, 24.7, 24.3, 21.2, 10.2

Thiazolidine 2,4-dion-3-yl (19.5%); amorphous; HRMS 347.1478, calcd.347.1426

¹³ C-NMR 171.9, 171.6, 161.3, 157.6, 109.6, 60.9, 57.8, 54.7, 48.9,43.9, 43.6, 33.7, 32.2, 24.9, 24.5

meso-3,4-Dimethylsuccinimido (50%); crystallized from CH₂ Cl₂:isopropanol; mp 141°-142° C.; TLC Rf 0.56.

¹³ C-NMR (250 MHz) 179.7, 161.5, 157.7, 109.5, 61.1, 58.0, 54.8, 49.0,43.7, 43.0, 40.6, 32.3, 25.0, 24.5, 15.2

3-Methylsuccinimido (46.5%); crystallized from CH₂ Cl₂ :isopropanol; mp168°-172° C.; TLC Rf 0.51; HRMS 344.2011, calcd. 344.2086.

¹³ C-NMR (250 MHz) 180.7, 176.7, 161.5, 157.1, 109.6, 61.1, 58.1, 54.8,49.0, 43.7, 40.7, 36.5, 34.6, 32.3, 25.0, 24.5, 17.0

3-Methylimidazolidine-2,5-dione-1-yl (28.9%); crystallized from ether;mp 106°-108° C.; TLC Rf 0.42; HRMS 344.1968, calcd. 344.1960.

¹³ C-NMR 170.0, 161.3, 157.7, 157.1, 109.5, 61.0, 57.9, 54.8, 51.6,48.9, 43.6, 40.9, 32.5, 29.6, 24.8, 24.4

3-Azabicyclo[3.2.1]octane-2,4-dion-3-yl (21%); TLC Rf 0.44; HRMS369.2205, calcd. 369.2167.

¹³ C-NMR 161.2, 157.6, 109.4, 60.9, 58.3, 54.7, 48.8, 44.8, 44.7, 43.5,40.5, 32.5, 32.4, 27.1(2), 24.8, 24.7

Piperidine-2,6-dion-1-yl (10%); crystallized from CH₂ Cl₂ : hexane; mp146°-148° C.; TLC Rf 0.37; HRMS 343.2011, calcd. 343.2011.

¹³ C-NMR 172.7, 161.4, 157.7, 109.5, 61.1, 58.5, 54.8, 48.9, 43.6, 41.4,33.0, 32.7, 25.0, 24.8, 17.2

4,4-Dimethlylpiperidine-2,6-dion-1-yl (14.5%); crystallized from ethylacetate; mp 212°-213° C.; TLC Rf 0.51; HRMS 371.2276, calcd. 371.2322.

¹³ C-NMR 172.2, 161.4, 157.7, 109.5, 61.1, 58.6, 54.9, 48.9, 46.5, 43.6,41.5, 32.9, 29.0, 27.7, 25.1, 24.8

8-Aza-spiro[4.5]decane-7,9-dion-8-yl (31.9%); crystallized fromisopropanol; mp 172°-173° C.; TLC Rf 0.49; HRMS 397.2450, calcd.397.2480.

¹³ C-NMR (250 MHz) 172.4, 161.4, 157.7, 109.5, 61.1, 58.5, 54.9, 48.9,45.0, 43.5, 41.5, 39.4, 37.6, 32.9, 25.0, 24.7, 24.2

5,5-Dimethyloxazolidine-2,4-dione-3-yl (20.8%); crystallized from ethylacetate:hexane; mp 162°-163° C.; TLC Rf 0.65; HRMS 359.1936, calcd.359.1957.

¹³ C-NMR 176.1, 161.2, 157.5, 154.6, 109.5, 83.2, 60.8, 57.5, 54.6,48.8, 43.5, 41.5, 32.0, 24.6, 24.3, 23.5, 23.4

Imidazolidine-2,5-dione-1(33.6%); crystallized from CH₂ Cl₂ : ether; mp191°-192° C.; TLC Rf 0.30; HRMS 330.1804, calcd. 330. 1804

¹³ C-NMR 171.8, 161.3, 159.1, 157.6, 109.6, 61.0, 57.7, 54.7, 48.9,46.4, 43.5, 40.4, 32.4, 24.7, 24.4

3,3-Dimethylsuccinimido (55.6%); crystallized from CH₂ Cl₂ : isopropylether; mp 145°-147° C.; TLC Rf 0.53; HRMS 357. 2126, calcd. 357. 2164.

¹³ C-NMR 183.4, 175.9, 161.3, 157.6, 109.5, 61.0, 57.9, 54.7, 48.8,43.5(2), 40.4, 39.8, 32.2, 25.6, 24.8, 24.4

Pyrazolo (23.8%); crystallized from ether; mp 86°-88° C.; TLC Rf 0.46;HRMS 298.1895, calcd. 298.1906

¹³ C-NMR 161.3, 157.8, 139.4, 129.8, 109.7, 104.8, 61.0, 56.6, 54.7,53.0, 49.0, 43.6, 34.6, 25.0, 24.7

1,2,4-Triazol-1-yl (62.3%); crystallized from ethyl acetate:hexane; mp150°-152° C.; TLC Rf 0.37; HRMS 299.1853, calcd. 299.1858.

¹³ C-NMR 161.3, 157.6, 152.0, 145.7, 109.8, 60.9, 56.2, 54.6, 50.4,48.9, 43.6, 33.9, 24.9, 24.6

4,4-Dimethylimidazolidine-2,5-dion-1-yl (25%); crystallized from CH₂ Cl₂:ether, mp 189°-190° C.; TLC Rf 0.35; HRMS 358.2074, calcd. 358.2000.

¹³ C-NMR 177.8, 161.2, 157.6, 156.9, 109.5, 60.9, 58.4, 57.6, 54.6,48.8, 43.5, 40.0, 32.3, 25.0, 24.6, 24.3

Tetrazol-2-yl (30.5%); amorphous; TLC Rf 0.64; HRMS 300.1792, calcd.300.1809.

¹³ C-NMR 161.2, 157.5, 152.8, 109.6, 60.8, 56.6, 54.5, 54.1, 48.8, 43.5,34.3, 24.9, 24.4

4,5-Dihydro-1H, 3H-pyrimidine-2,6-dion-1-yl (46%); crystallized fromisopropanol:ether, mp 190°-192° C.; TLC Rf 0.36; HRMS 344.1919, calcd.344.1960.

¹³ C-NMR 169.8, 161.4, 157.7, 155.5, 109.5, 61.1, 58.4, 54.9, 48.9,43.6, 42.0, 35.3, 33.0, 31.8, 25.4, 24.8

5-Methyl-4,5-dihydro-1H, 3H-pyrimidine-2,6-dione-1-yl (23%);crystallized from ethanol; mp 201°-202° C.; TLC Rf 0.35; HRMS 358.2118,calcd. 358.2117.

¹³ C-NMR 172.9, 161.4, 157.7, 155.4, 109.5, 61.1, 58.4, 54.9, 48.9,43.6, 42.4, 42.3, 42.1, 35.8, 33.2, 33.0, 24.9, 13.4 (extra peaks due todiastereomers)

4-Methyl-4,5-dihydro-1H, 3H-pyrimidine-2,6-dione-1-yl (55%);crystallized from CH₂ Cl₂ :ether; mp 202°-208° C.; TLC Rf 0.38; HRMS358.2128, calcd. 358.2117.

¹³ C-NMR 169.6, 161.4, 157.7, 155.2, 109.5, 61.1, 58.4, 54.9, 48.9,43.5, 42.4, 42.0, 39.3, 33.2, 32.9, 24.9, 24.8, 20.8 (excess peaks dueto diastereomers)

EXAMPLE 3 cis-7-(Substituted methyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazines

Substituting the analogous 2-(2-pyridyl)mesylate ester for the2-(2-pyrimidinyl)mesylate ester, the following additional titlecompounds (specified as in the preceding Example) were prepared byMethod A of Example 1.

3-Methylimidazolidine-2,5-dion-1-yl (8.9%); crystallized from CH₂ Cl₂:isopropyl ether; mp 142°-143° C.; TLC Rf 0.43; HRMS 343.1978, calcd.343.2018.

¹³ C-NMR 170.0, 159.2, 157.0, 147.8, 137.3, 112.8, 106.8, 60.7, 57.7,54.6, 51.5, 50.5, 45.0, 40.7, 32.5, 29.5, 24.7, 24.5

4,4-Dimethylpiperidine-2,6-dion-1-yl (31.7%); crystallized from ether;mp 134°-135° C.; HRMS 370.2321, calcd. 370.2368.

¹³ C-NMR 172.2, 159.3, 147.9, 137.4, 112.9, 106.9, 60.9, 58.5, 54.8,50.6, 46.5, 45.0, 41.5, 32.9, 29.1, 27.7, 25.1, 24.9

Succinimido (36.3%); crystallized from CH₂ Cl₂ :ether; mp 164°-165° C.;TLC Rf 0.41; HRMS 328.1880, calcd. 328.1899.

¹³ C-NMR 177.4, 159.2, 147.8, 137.3, 112.9, 106.8, 60.7, 57.9, 54.6,50.5, 45.0, 40.6, 32.1, 28.1, 24.8, 24.5

8-Azospiro[4.5]decane-7,9-dion-8-yl (25.3%); TLC Rf 0.42 (ethylacetate); HRMS 396.2562, calcd. 396.2525.

¹³ C-NMR 172.4, 159.3, 147.9, 137.3, 112.9, 106.9, 60.9, 58.5, 54.8,50.6, 45.0(2), 41.5, 39.3, 37.6, 32.9, 25.0, 24.9, 24.2

5,5-Dimethyloxazolidine-2,4-dion-3-yl (27.3%); crystallized from CH₂ Cl₂:ether; mp 171°-173° C.; HRMS 358.2040, calcd. 358.2005; TLC Rf 0.56.

¹³ C-NMR 176.3, 159.2, 154.8, 147.9, 137.4, 113.0, 106.9, 83.4, 60.7,57.5, 54.6, 50.6, 45.1, 41.6, 32.1, 24.7, 24.5, 23.6(2)

4-Methylsuccinimido (28%); crystallized from isopropyl alcohol; mp145°-150° C.; TLC Rf 0.47; HRMS 342.2036, calcd. 342.2056.

¹³ C-NMR 180.8, 176.6, 159.3, 147.9, 137.4, 113.0, 106.9, 60.9, 58.0,54.7, 50.7, 45.1, 40.6, 36.4, 34.6, 32.3, 24.9, 24.6, 16.9

Tetrazolo (36%); amorphous; TLC Rf 0.48 (ethyl acetate); HRMS 299.1778,calcd. 299.1859.

¹³ C-NMR 159.1, 152.7, 147.8, 137.3, 113.0, 106.9, 60.6, 56.6, 54.4,54.1, 50.5, 45.1, 34.3, 24.9, 24.5

4,4-Dimethylsuccinimido (40%); crystallized from ethyl acetate:hexane;TLC Rf 0.45 (ethyl acetate); HRMS 356.2230, calcd. 356.2218

¹³ C-NMR 183.5, 176.0, 159.3, 147.9, 137.4, 113.0, 106.9, 60.9, 57.9,54.7. 50.6, 45.1, 43.6, 40.6, 39.9, 32.3, 25.6(2), 24.8, 24.6

4,4-Dimethylimidazolidine-2,5-dion-1-yl (37%); crystallized from CH₂ Cl₂; isopropyl ether; mp 170°-171° C.; TLC Rf 0.28 (ethyl acetate); HRMS357.2203, calcd. 357.2166

¹³ C-NMR 177.8, 159.3, 157.0, 147.9, 137.5, 113.0, 107.0, 60.9, 58.6,57.7, 54.7, 50.7, 45.1, 40.3, 32.5, 25.1(2), 24.7, 24.6

Imidazolidine-2,5-dion-1-yl (45%); TLC Rf 0.22; HPMS 329.1903, calcd329.1854.

¹³ C-NMR 171.9, 159.3, 159.1, 147.8, 137.5, 113.1, 107.1, 60.8, 57.7,54.6, 50.7, 46.5, 45.1, 40.5, 32.4, 24.7, 24.6

1,2,4-Triazol-1-yl (18.7%); crystallized from isopropyl ether:hexane; mp109°-110° C.; HRMS 298.1943, calcd. 298.1906; TLC Rf 0.37.

¹³ C-NMR (250 MHz) 159.2, 152.1, 147.9, 143.6, 137.4, 113.2, 107.0,60.8, 56.2, 54.6, 50.6, 50.5, 45.2, 33.9, 25.0, 24.7

Piperidine-2,6-dion-1-yl (22.8%); crystallized from CH₂ Cl₂ : isopropylether; mp 114°-115° C.; TLC Rf 0.44; HRMS 342.2043, calcd. 342.2055.

¹³ C-NMR (250 MHz) 172.8, 159.3, 147.9, 137.4, 112.9, 106.9, 60.9, 58.4,54.8, 50.6, 45.0, 41.5, 33.0, 32.8, 25.0(2), 17.2

4-Methyl-4,5-dihydro-1H,3H-primidine-2,6-dion-1-yl (47%); crystallizedfrom isopropanol; mp 184°-186° C.; TLC Rf 0.35; HRMS 357.2155, calcd.357.2164.

¹³ C-NMR 169.6, 159.3, 155.0, 147.9, 137.4, 112.9, 106.9, 60.9, 58.3,54.8, 50.6, 45.0, 42.4, 42.1, 39.4, 33.2, 32.9, 24.9, 20.8 (excess peaksdue to diasteromers).

5-Methyl-4,5-dihydro-1H,3H-pyrimidine-2,6-dione-1-yl (40%) crystallizedfrom isopropanol; mp 182°-183° C.; TLC Rf 0.34; HRMS 357.2147, calcd.357.2165.

¹³ C-NMR 172.9, 159.4, 155.5, 147.9, 137.4, 113.0, 107.0, 60.9, 58.4,54.8, 50.6, 45.1, 42.4, 42.3, 42.0, 35.7, 33.3, 33.0, 25.0, 13.4

Dihydro-1H,3H-pyrimidine-2,6-dione-1-yl (67%); crystallized fromisopropanol; mp 190°-191° C.; TLC Rf 0.28, HRMS 343.1975, calcd.343.2011.

¹³ C-NMR 169.8, 159.4, 155.4, 147.9, 137.4, 113.0, 107.0, 60.9, 58.3,54.8, 50.6, 45.1, 42.0, 35.3, 33.0, 31.8, 25.0, 24.9.

Thiazolidine-2,4-dion-3-yl (63%); crystallized from isopropanol; mp159°-160° C.; TLC Rf 0.47 (19:1 ethyl acetate:CH₃ OH); HRMS 346.1528,calcd. 346.1463.

¹³ C-NMR 171.9, 171.7, 159.3, 148.0, 137.5, 113.1, 107.0, 60.8, 57.8,54.6, 50.6, 45.1, 44.0, 33.7, 32.2, 24.9, 24.6.

EXAMPLE 4cis-7-(Succinimidomethyl)-2-(2-pyridyl)-2,3,4,6,7,9,9a-octahydro-1H-Pyrido[1,2a]pyrazine

By method B of Example 1,cis-7-(hydroxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octrahydro-1H-pyrido[1,2-a]pyrazine(247 mg, 1.0 mmol) and succinimide were converted to 231 mg (70%) ofpresent title product as crystals from isopropyl alcohol, identical tothe material prepared in the preceding Example.

EXAMPLE 5cis-7-[(8-azaspiro[4.5]decane-7,9-dion-8-yl)methyl]-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

By method C of Example 1,cis-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-H-pyrido-[1,2-a]pyrazine(142 mg, 0.57 retool) and 3,3-tetramethyleneglutaric anhydride (96 mg,0.57 mmol) were converted to 105 mg (46%) of present title product ascolorless crystals from isopropyl alcohol, identical to the materialprepared in Example 2.

EXAMPLE 6 (7S, 9aS)-2-(2-Pyrimidyl)-7-(succinimidomethyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

A mixture of(7R,9aS)-7-(Aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octrahydro-1H-pyrido-[1,2-a]pyrazine(6.30 g, 0.025 mol) and succinic anhydride (2.80 g, 0.028 mol) in 280 mlof mixed xylenes (b.p. 139°-143° C.) was heated to 100° C., at whichpoint dimethylformamide (4 ml) was added to affect complete solution.Using a Dean-Stark trap, the mixture was vigorously refluxed for twohours. The reaction solution was decanted from a tarry residue andconcentrated in vacuo to amorphous solids, which were transferred to awell-stirred mixture of methylene chloride and water (250 ml of each)and the pH adjusted to 11 with 6N NaOH. The organic phase was separated,dried (Na₂ SO₄), and concentrated in vacuo to a colorless foam (6.4 g).Crystallization of the entire sample from hot isopropyl alcohol (250 ml)afforded 4.7 g (56%) of present title product, mp 211°-212° C.;[alpha]_(D) ²⁵ =-35° (CH₂ Cl₂). HRMS 329.1809, calcd. 329.1854. The ¹³C-NMR was identical to that of the racemic product of Example 1.

Alternatively 5.0 mg (17%) of identical product, likewise crystallizedfrom isopropanol, was prepared from (7S,9aS)-7-(hydroxymethyl)-2-(2-pyrimidinyl)2,3,4,6,7,8,9,9a-octahydro[1,2-a]pyrazine(17.1 mg, 0.069 mol) by Method A of Example 1.

EXAMPLE 7 cis-7-(Pyrazolomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

cis-7-(Methanesulfonyloxymethyl)-2-(2-pyridyl)2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (350 mg, 1.0 mmol), pyrazole (439 mg, 6.5 mmol) andsodium carbonate (228 mg, 2.2 mmol) and 15 ml of acetonitrile wererefluxed for 18 hours. The reaction mixture was cooled, stripped ofsolvent and the residue distributed between 20 ml each of CH₂ Cl₂ andwater. The well-stirred, 2-phase mixture was adjusted to pH 10 withsaturated Na₂ CO₃. The aqueous layer was extracted 1×20 ml from CH₂ Cl₂.The organic layers were combined, dried (Na₂ SO₄) and stripped tosolids, which were flash chromatographed on 6 g of silica gel with ethylacetate as eluant to yield 134 mg (42%) of title product as an amorphoussolid. TLC Rf 0.43 (9:1 CH₂ Cl₂ :CH₃ OH); HRMS 297.1962, calcd.297.1957.

¹³ C-NMR (300 MHz, CDCl₃) delta 159.3, 147.9, 139.3, 137.4, 129.8,113.1, 107.0, 104.9, 60.9, 56.6, 54.6, 53.1, 50.7, 45.2, 34.7, 25.0,24.9.

PREPARATION 1 Dimethyl Pyridine-2,5-dicarboxylate

To a stirred slurry of 2,5-pyridinedicarboxylic acid (2407 g; 14.4 mol)in methanol (8.0 liter) at -5° to -10° C. thionylchloride (3430 g; 2.10liters; 28 8 mol) was added dropwise while maintaining the temperaturein the -5° to -10° C. range. After completing the addition, the reactionwas allowed to warm to ambient temperature, and stirred for 18 hours.The resulting solution was concentrated in vacuo to a volume of 4liters, and an equal volume of water was added. The pH of thewell-stirred mixture was then adjusted to 10 with saturated aqueoussodium carbonate. Solids were removed by filtration. The organic layerof the filtrate was separated, washed with water (8 liters), and driedin vacuo to afford the title compound (2250 g; 80% yield) as anamorphous solid.

PREPARATION 2 Dimethyl cis- and trans-Piperidine-2,5-dicarboxylateAcetate

The product of the preceding Preparation (2250 g; 11.53 mol) in glacialacetic acid (25 liters) was hydrogenated in the presence of 57 gplatinum oxide as catalyst at 3.52 kg/cm² pressure for 18 hours. Thecatalyst was recovered by filtration, and the filtrate concentrated invacuo to afford a mixture of title acetate salts as a viscous ambersyrup (2300 g, 100% yield), sufficiently pure for use directly in thenext step.

PREPARATION 3 Dimethyl cis- andtrans-1-(Cyanomethyl)piperidine-2,5-dicarboxylate

A well-stirred mixture of title product of the preceding Preparation(3000 g, 11.53 mol), chloroacetonitrile (1.00 kg; 13.25 mol; 1.1equivalents), sodium carbonate (8.00 kg; 75.5 mol; 6.5 equivalents), andpotassium iodide (320 g; 1.90 mol; 0.17 equivalents) in methylisobutylketone (36 liters), was refluxed vigorously for 18 hours. The reactionwas cooled to room temperature, and solids were removed by suctionfiltration. The filter cake was extracted, first with methyisobutylketone (12 liters), and then with methylene chloride (30 liters). Theoriginal filtrate and both filtered extracts were combined and thenconcentrated in vacuo to afford the mixed title products (1400 g; 51%yield) as an amber oil.

PREPARATION 4 Methylcis-1-Oxo-2,3,4,6,7,8,9,9a-octahydro-1H-Pyrido[1,2-a]pyrazine-7-carboxylate

Title product of the preceding Example (60.0 g, 0.25 mol) in methanol (1liter) and ethyl acetate (0.4 liter) was hydrogenated over Raney nickel(washed with water to pH 9 on a filter funnel; 93 g water wet) at 3.52kg/cm² pressure for 18 hours. The catalyst was filtered, and thefiltrate was concentrated in vacuo to an oil. Overnight crystallizationfrom a methylene chloride/isopropyl ether (90 ml/120 ml respectively)afforded exclusively the desired cis isomer (title product) as colorlesscrystals, mp 166°-168° C. (dec.), (24.99 g; 47% yield); HRMS 212.1156,calcd. 212.1162.

¹³ C-NMR (300 MHz, CDCl₃) delta 173.9, 171.2, 64.8, 64.7, 56.3, 56.2,51.7, 50.8, 40.6, 39.5, 25.0, 24.4

PREPARATION 5cis-7-Hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-alpyrazine

A flame-dried flask fitted with a magnetic stirrer, condenser, andnitrogen inlet was charged with a slurry of lithium aluminum hydride(14.88 g, 0.46 mol) in 500 ml of dry tetrahydrofuran. Title product ofthe preceding Preparation (53.61 g, 0.25 mol) was added portionwise, insolid form, to the well-stirred mixture over a one hour period. Themixture was then reluxed under nitrogen for 18 hours. After cooling to15° C. the reaction was quenched by cautious dropwise addition of water(100 ml). The mixture was then filtered, and the filter cake was washedwith 150 ml of tetrahydrofuran. The filtrate was concentrated in vacuoto a solid, which was extracted three times with one liter portions ofmethylene chloride. The tetrahydrofuran and methylene chloride extractswere concentrated in vacuo to afford the title compound (42.06 g, 97.8%yield) as an amorphous solid. HRMS 170.14 13, calcd. 170. 1419.

¹³ C-NMR (300 MHz, CDCl₃) delta 65.6, 62.6, 57.8, 56.0, 51.8,45.8, 34.7,26.4, 26.0

PREPARATION 6cis-7-Hydroxymethyl-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1Hpyrido[1,2-a]pyrazine

A solution consisting of title product of the preceding preparation(19.7 g; 0.12 mol), sodium carbonate (30.45 g; 0.29 mol) and2-chloropyrimidine (13.6 g; 0.12 mol) in water (150 ml) was stirred andheated at 95° C. for 14 hours. The reaction mixture was cooled, and thenextracted with 200 ml of methylene chloride. The organic extract waswashed with water and then with brine (200 ml of each), stirred withactivated carbon, filtered, dried (anhydrous sodium sulfate, andconcentrated to an amber oil. Crystallization of the entire sample frommethylene chloride/hexane (45 ml/150 ml, respectively) afforded 21.5 g(76.7% yield) of the title compound as colorless crystals, mp 135°-136°C. HRMS 248.1622, calcd. 248.1637. TLC Rf 0.3 (CH₂ Cl₂ :CH₃ OH 9:1).

¹³ C-NMR (300 MHz, CDCl₃) delta 161.2, 157.6, 109.7, 65.5, 60.9, 57.3,54.8, 48.9, 43.4, 34.8, 26.1, 25.8

PREPARATION 7cis-7-(Methanesulfonyloxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1-pyrido[1,2-a]pyrazine

To a well-stirred solution of the title product of the precedingPreparation (1.5 g; 6.0 mmol) and triethylamine (1.68 ml, 12 mol) inmethylene chloride (28 ml) chilled to 5° C., a solution ofmethanesulfonyl chloride (0.70 ml; 9.0 mmol) in methylene chloride (7ml) was added dropwise over 15 minutes. Within 10 minutes of stirring(5° C.) following the methane-sulfonylchloride addition, inspection of areaction aliquot by thin layer chromatography (silica gel plates;elution with methylene chloride/methanol=9.1 by volume; UV detection)showed complete reaction. Water (50 ml) was added to the reactionmixture, and the pH of the well-stirred mixture was adjusted to 9.5 withsaturated sodium carbonate. The organic phase was separated, washed fivetimes with 150 ml portions of water, dried (anhydrous sodium carbonate),and concentrated in vacuo to afford the title compound (1.87 g, 95.4%yield), sufficiently pure for use in the next step without furtherpurification. The entire sample was dissolved in 3 ml of hot methylenechloride, to which hexane was added dropwise (ca 3 ml) until thesolution became turbid. Stirring for one hour afforded 1.10 g ofcrystalline title product (colorless crystals), mp 141°-142° C.

¹³ C-NMR (250 MHz, CDCl₃) delta 161.3, 157.6, 109.7, 71.1, 60.8, 55.7,54.6, 48.9, 43.5, 36.9, 33.4, 24.7, 24.2

PREPARATION 8cis-7-Hydroxymethyl-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a)pyrazine

A mixture consisting of title product of Preparation 5 (9.10 g; 53.4mmol), sodium carbonate (14.1 g; 0.13 mol), and 2-bromopyridine (25.5ml; 42.3 g; 0.27 mol) in isoamylalcohol (25 ml) was refluxed for 72hours. The reaction was filtered while hot, and the filter cake washedwith 50 ml of methylene chloride. The filtrate was concentrated in vacuoto an oil, which was taken up in 100 ml ethyl acetate. An equal volumeof water was added, and the pH of the well-stirred mixture was adjustedto 11.5 (saturated sodium carbonate). The organic phase was separated,treated with activated carbon, dried (anhydrous sodium sulfate), andconcentrated in vacuo to an oil. Flash chromatography of the entiresample (125 g silica gel, 32-63 mesh; elution with methylenechloride/methanol=97:3 by volume) with TLC monitoring of fractions[product R_(f) =0.26 (methylene chloride:methanol 9:1 in volume),detection by U.V. and Dmgendorf's spray] afforded 7.50 g (56.6% yield)of the title compound as a pale yellow amorphous solid.

¹³ C-NMR (300 MHz, CDCl₃) delta 159.1, 147.8, 137.4, 113.2, 107.0, 65.8,60.7, 57.3, 54.7, 50.6, 45.0, 34.7, 26.2, 26.0

PREPARATION 9 cis-7-(Methanesulfonyloxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

By the method of Preparation 7, the title product of the precedingExample (240 mg, 0.97 mmol) was converted to present title product (0.30g, 94.7%) as a colorless oil. TLC Rf 0.34 (ethyl acetate). RMS 325.1475, calcd. 325. 1460.

¹³ C-NMR (250 MHz, CDCl₃) delta 159.2, 147.9, 137.5, 113.2, 107.1, 71.2,60.7, 55.7, 54.6, 50.7, 45.2, 37.0, 33.5, 24.9, 24.2

PREPARATION 10cis-7-(Pthalimido)methyl-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

Method A

By Method A of Example 1, phthalimide (4.13 g, 36.5 mmol) and the titleproduct of Preparation 7 (7.93 g, 2.43 mmol) was converted to presenttitle product, as colorless crystals from warm isopropyl alcohol (1.86g, 20%); mp 161°-162° C. HRMS 377.1815, calcd. 377. 1852.

¹³ C-NMR (300 MHz, CDCl₃) delta 168.4, 161.3, 157.6, 133.8, 132.0,123.0, 109.5, 61.0, 57.8, 54.7, 48.9, 43.5, 39.8, 32.9, 24.8, 24.4

Method B

By Method B of Example 1, phthalimide (147 mg, 1.0 mmol) and the titleproduct of Preparation 6 (248 mg, 1.0 mmol) were converted to 31 mg(9.5%) of identical title product.

PREPARATION 11cis-7-(Azidomethyl)-2-(2-pyrimidyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

Title product of Preparation 7, (57.1 g; 0.175 mol) and sodium azide (75g; 1.1 mol) in dry dimethylformamide (500 ml) was stirred 17 hours at100° C. (oil bath). Stirring and heating was stopped, and the slurry ofexcess sodium azide was allowed to settle. The supernatant was carefullydecanted, and then concentrated in vacuo to a light yellow oil. Theresidual sodium cake was extracted twice with 500 ml portions ofmethylene chloride. The oil was dissolved in the combined methylenechloride extracts. An equal volume of water was added, and the pH of thewell-stirred mixture adjusted to 11.5 (6N sodium hydroxide). The organicphase was separated, dried (anhydrous sodium sulfate), and concentratedin vacuo to afford 48.2 g of title compound as a light-yellow oil. TLCRf 0.53 (ethylacetate). HRMS 273.1735, calcd. 273.1705.

¹³ C-NMR (250 MHz, CDCl₃) delta 161.3, 157.6, 109.6, 60.9, 56.7, 54.6,52.8, 48.9, 43.5, 33.7, 25.3, 24.7

PREPARATION 12cis-7-(Aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1-pyrido[1,2-a]pyrazine

Method A

A suspension of the title product of Preparation 10 (1.86 g; 4.9 mmol)in ethanol (15 ml) and anhydrous hydrazine (0.156 ml; 158 mg; 4.9 mmol)was refluxed for 2.5 hours. The mixture was concentrated in vacuo to anoil. Concentrated hydrochloric acid (10 ml) was added, and the mixturerefluxed for 3.5 hours. The reaction was filtered and the filtrate wasconcentrated in vacuo to a solid, all of which was dissolved in 15 ml ofwater and the pH adjusted to 10.0 (6N sodium hydroxide). The basicsolution was extracted with 5×50 ml of methylene chloride, and theorganic extracts combined, dried (anhydrous sodium sulfate) andconcentrated in vacuo to afford 1.07 g (88%) of present title product asan amber oil. TLC Rf 0.50 (CH₂ Cl₂ :CH₃ OH:conc. NH₃ 3:1:0.3). HRMS247.1784, calcd. 247. 1787.

¹³ C-NMR (300 MHz, CDCl₃) delta 161.3, 157.6, 109.5, 61.1, 57.0, 54.9,48.9, 43.4, 42.9, 36.6, 25.6, 24.9

Method B

A solution of the title product of the preceding Preparation (48.0 g;0.176 mol) in 800 ml of ethanol and 70 ml of ethyl acetate washydrogenated at a pressure of 3.5 kg/cm² in the presence of 24 g of 5%palladium-on-carbon catalyst for 2 hours. Filtration of the catalyst andin vacuo concentration of the filtrate afforded 34.8 g (80%) of titlecompound as a colorless oil which crystallized upon standing, with theproduct of method A.

PREPARATION 13cis-7-(Pthalimido)methyl-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

By method B of Example 1, pthalimide (0. 595 g, 4.1 mmol) and titleproduct of Preparat ion 8 (1.00 g, 4.1 mmol) were converted to 1.02 g(67%) of present title product as colorless crystals from isopropanol,mp 167°-168° C. HRMS 3 76.1900, calcd. 376.1900.

¹³ C-NMR (300 MHz, CDCl₃) delta 168.6, 159.3, 147.9, 137.4, 133.9,132.1, 123.2, 113.0, 107.0, 60.9, 57.8, 54.7, 50.7, 45.1, 39. 9, 33.0,24.9, 24.6

PREPARATION 14cis-7-(Azidomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

By the method of Preparation 11, title product of Preparation 9 (1.0 g,3.06 mmol) was converted to 0.70 g (84%) of present title product as acolorless oil. HRMS 272.1739, calcd. 272.1750

¹³ C-NMR (300 MHz, CDCl₃) delta 159.2, 147.7, 137.2, 112.8, 106.8, 60.9,56.9, 54.8, 50.5, 44.9, 43.1, 37.0, 25.6, 25.0

PREPARATION 15cis-7-(Aminomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

By Method A of Preparation 12, title product of Preparation 13 (0.484 g,1.29 mmol) was converted to 0.311 g (98%) of present title product as acolorless, viscous oil. TLC Rf 0.51 (CH₂ Cl₂ :CH₃ OH: conc. NH₃3:1:0.3). HRMS 246.1861, calcd. 246.1844.

Identical product (0.60 g, 95%) was prepared from title product of thepreceding Preparation (0.70 g, 2.6 mmol) by Method B of Preparation 12.

PREPARATION 16(7R-9aS)-7-(Aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

To a solution of the title product of Preparation 12 (33.54 g, 0.136mol) in 1.44 l of near-boiling isopropanol, (-)-mandelic acid (20.63 g,0.136 mol) was added with stirring to effect total dissolution. Thestirred solution was allowed to cool slowly to ambient temperature; and24 hours later a heavy crystalline mass was isolated by suctionfiltration, and dried in vacuo. The entire sample was dissolved in 1.85l of hot isopropanol, and the resulting solution was allowed to cool toambient temperature, and stir at that temperature for 72 hours, duringwhich time, a heavy colorless crystalline mass formed. [14.0 g, 51.7%yield of the (-)-mandelic acid salt of present title product, mp202°-203° C. (dec.)]. The entire sample was dissolved in water (200 ml).An equal volume of methylene chloride was added, and the pH of thewell-stirred mixture was adjusted to 9.5 with 6N NaOH. The organic phasewas separated, dried, and concentrated in vacuo to afford 6.30 g (37.6%)of present title product as a colorless solid.

[alpha]_(D) ²⁵ =36.7° in methylene chloride (C=0.0337 g/ml)]

The title product of the preceding Preparation is resolved by the samemethod to form (7R,9aS)-7-(Aminomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.

PREPARATION 17(7S-9aS)-7-(Acetoxymethyl)-2-(2-pyrimidinyl)-2,3,4,5,6,7,8,9,9a-octahydro-1-pyrido[1,2-a]pyrazine

To title product of the preceding Preparation (180.4 mg, 0.73 mmol) in 2ml of CHCl₃ was added acetic acid (0.125 ml, 2.19 mmol) and isoamylnitrite (0.108 ml, 0.802 mmol). The resulting mixture was refluxed for 4hours, cooled, diluted with 25 ml CHCl₃ and then 10 ml H₂ O, andadjusted to pH 10 with saturated Na₂ CO₃. The aqueous layer wasseparated and extracted with 20 ml CH₂ Cl₂. The organic layers werecombined, treated with activated carbon, dried (Na2SO₄) and stripped toyield 188.5 mg of an oil, which was chromatographed on silica gel using500 ml of 3:2 ethyl acetate:hexane as eluant, monitored by TLC (ethylacetate). Desired product fractions (Rf 0.30) were combined and strippedto yield 58.5 mg (28%) of present title product.

[alpha]_(D) ²⁵ =-35.9° (CH₂ Cl₂). HRMS 290.1752, calcd. 290.1742.

¹³ C-NMR (300 MHz, CDCl₃) delta 171.2, 161.4, 157.7, 109.6, 65.5, 61.0,56.4, 54.8, 48.9, 43.5, 33.0, 24.9, 24.7, 21.1

By the same method the 2-(2-pyridyl) derivative of the precedingPreparation is converted to (7S,9aS-7-(acetoxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9a-octahydro-1H-pyrido[1,2-a]pyrazine.

PREPARATION 18 (7S,9aS)-7-(Hydroxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1-pyrido[1,2-a]pyrazine

Title product of the preceding Preparation (51.4 mg, 0.177 mmol) wasdissolved in 1 ml of 1:1 H₂ O:CH₃ OH, and 6N NaOH (0.06 ml, 3.6 mmol)was added. After stirring for 3 hours, the mixture was stripped of CH₃OH, the aqueous residue diluted with 25 ml CH₂ Cl₂ and 10 ml H₂ O, andthe pH of the 2 phase system adjusted to 10. The separated aqueous layerwas extracted 2×10 ml CH₂ Cl₂, and the organic layers combined, dried(Na₂ SO₄), stripped and the residue crystallized from CH₂ Cl₂ andisopropyl ether to yield 27 mg of title product mp 160°-162° C.

[alpha]_(D) ²⁵ =-34.2° (CH₂ Cl₂) HRMS 248.1647, calcd. 248.1638.

By the same method, the pyridyl analog of the preceding Preparation isconverted to (7S,9aS)-7-(hydroxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.

PREPARATION 19(7S-9aS)-7-(Methanesulfonyloxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

By the method of Preparation 9, the title product of the precedingPreparation (20.5 mg) was converted to present title product inessentially quantitative yield. TLC Rf 0.50 (9:1CH₂ Cl₂ :CH₃ OH).

By the same method, the pyridyl analog of the preceding Preparation isconverted to (7S,9aS)-7-(methanesulfonyloxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazole.

I claim:
 1. A method of treating substance abuse or addiction in ahuman, wherein said substance abuse or addiction is selected from thegroup consisting of alcohol and nicotine abuse or addiction, whichcomprises administering to said human an effective amount of a racemicor optically active compound of the formula ##STR11## orpharmaceutically acceptable acid addition salt thereof, wherein X is Nor CH;Y is ##STR12## ##STR13## SCH₂, OCH₂, --Y¹ (CH₂)_(a) --wherein the(CH₂)_(n) portion of said --Y¹ (CH₂)_(n) -- is optionally substitutedwith 1 or 2 methyl groups; n is 1 or 2; and Y¹ is CH₂, NH or NCH₃.
 2. Amethod of claim 1 wherein X is N.
 3. A method of claim 1 wherein Y is##STR14##
 4. A method of claim 3 wherein X is N.
 5. A method of claim 1wherein the compound is optically active.
 6. A method of claim 2 whereinthe compound is optically active.
 7. A method of claim 4 wherein thecompound is optically active.
 8. A method of claim 4 wherein thecompound is racemic and Z is --Y¹ (CH₂)_(n) -- wherein the (CH₂)_(n)portion of said --Y¹ (CH₂)_(n) -- is optionally substituted with 1 to 2methyl groups.
 9. The method of claim 8 wherein Z is Y¹ (CH₂)_(n), Y¹ isCH₂ and n is
 1. 10. A method of claim 7 wherein Z is --Y¹ (CH₂)_(n) --wherein the (CH₂)_(n) portion of said --Y¹ (CH₂)_(n) -- is optionallysubstituted with 1 to 2 methyl groups.
 11. The method of claim 10wherein Z is Y¹ (CH₂)_(n), Y¹ is CH₂ and n is
 1. 12. A method of claim 3wherein Z is SCH₂ or OCH₂.
 13. A method of claim 3 wherein Z is Y¹(CH₂)_(n) and Y¹ is NH or NCH₃.
 14. A method of claim 1 wherein Y is##STR15##
 15. A method of claim 1 wherein X is CH.
 16. A method of claim15 wherein Y is ##STR16##
 17. The method of claim 1 wherein saidsubstance abuse or addiction is alcohol abuse or addiction.
 18. Themethod of claim 1 wherein said substance abuse or addiction is nicotineabuse or addiction.